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AND
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CONSEQUENCES
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Ketone Bodies
Ketone bodies can be regarded as water-soluble,
transportable form of acetyl units. Fatty acids are released by
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adipose tissue and converted into acetyl units by the liver,
which then exports them as ketone bodies.
Acetoacetate, D(-3) hydroxy butyrate (Beta hydroxy
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Ketogenesis
Ketogenesis takes place in liver using Acetyl co A as a
substrate or a precursor molecule.
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Enzymes responsible for ketone body formation are
associated mainly with the mitochondria
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Ketogenesis
Acetoacetyl CoA then reacts with acetyl CoA and water
to give 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) and
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CoASH.
The reaction is catalyzed by HMG co A synthase.
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This reaction, which has a favorable equilibrium
owing to the hydrolysis of a thioester linkage,
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place.
This occurs solely in liver and rumen epithelium,
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acid, acetoacetate also undergoes a slow, spontaneous
decarboxylation to acetone.
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D(-)3-hydroxybutyrate dehydrogenase.
D(-)-3-Hydroxybutyrate is quantitatively the predominant
ketone body present in the blood and urine in ketosis.
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acetoacetate, but such a thioesterase does not seem to
exist.
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across the inner mitochondrial membrane as well as
across the blood-brain barrier and cell membranes.
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synthesis, the ketones must be reconverted to acetyl CoA in the
mitochondria:
Utilization of Beta-hydroxybutyrate
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must be used.
In this case the energy comes from a trans esterification of
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Biochemistry For Medics
The liver has acetoacetate available to supply to other organs because it 14
lacks the particular CoA transferase and that is the reason that Ketone
bodies are synthesized in the liver but utilized in the peripheral tissues.
Liver v/s Peripheral tissues
for ketones as fuel molecules
The enzyme, Succniyl co A Acetoacetate co A transferase,
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also known as Thiophorase, is present at high levels in most
tissues except the liver.
Importantly, very low level of enzyme expression in the liver
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Ketosis does not occur unless there is an increase in the
level of circulating free fatty acids that arise from lipolysis of
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Biochemistry For Medics
Hormone sensitive lipase exists in two forms inactive
dephosphorylated (brought by Insulin) and active phosphorylated 17
form (brought by glucagon, ACTH and catecholamines). Insulin
promotes lipogenesis while the other hormones promote lipolysis.
Regulation of Ketosis
2) Fate of fatty acid-free fatty acids are either oxidized to CO2 or
ketone bodies or esterified to triacylglycerol and
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phospholipids.
There is regulation of entry of fatty acids into the oxidative
pathway by carnitine Acyl transferase-I (CAT-I)
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Biochemistry For Medics
CAT-I activity is low in the fed state, leading to depression 19
of fatty acid oxidation. However, CAT-1 activity is higher
in starvation, allowing fatty acid oxidation to increase.
Regulation of Ketosis
3) Fate of Acetyl co A
The acetyl-CoA formed in beta-oxidation is oxidized in the
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citric acid cycle, or it enters the pathway of ketogenesis to
form ketone bodies.
As the level of serum free fatty acids is raised,
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Regulation of Ketosis- Overview
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Biochemistry For Medics
21
During high rates of fatty acid oxidation, primarily in the liver, large
amounts of acetyl-Co A are generated. These exceed the capacity of
the TCA cycle, and one result is the synthesis of ketone bodies.
Biological significance of ketone
bodies
Ketone bodies serve as a fuel for extra hepatic tissues
Brain
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It is metabolically active and metabolically privileged.
The brain generally uses 60-70% of total body glucose
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energy.
Heart muscle and the renal cortex use acetoacetate in
preference to glucose.
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It is due to increased production of ketone bodies by the
liver rather than to a deficiency in their utilization by extra
hepatic tissues.
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Chronic alcoholism
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Certain conditions of alkalosis
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Clinical Significance-Ketoacidosis
Both -hydroxybutyrate and acetoacetate are organic acids.
and are released in the protonated form, to lower the pH of
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the blood.
In normal individuals, other mechanisms
compensate for the increased proton release.
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from the desire to lose weight rapidly, or
in clinical situations in which an individual cannot eat because
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Starvation induced ketosis
The decreased insulin to glucagon ratio, makes this period of
nutritional deprivation a catabolic state, characterized by
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degradation of glycogen, triacylglycerol and protein.
This sets in to motion an exchange of substrates between
liver, adipose tissue, muscle and brain that is guided by two
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primarily ketone bodies to
preserve glucose for use
by the brain.
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Diabetic Keto- acidosis
Diabetic Ketoacidosis (DKA) is a state of inadequate insulin levels
resulting in high blood sugar and accumulation of organic acids and
ketones in the blood.
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It is a potentially life-threatening complication.
It happens predominantly in type 1 diabetes mellitus,
But can also occur in type 2 diabetes mellitus under certain
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Gluconeogenesis, glycogenolysis, and Ketone body formation in the
liver, as well as increases in substrate delivery from fat and
muscle (free fatty acids, amino acids) to the liver
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Biochemistry For Medics
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Diabetic Ketoacidosis may be diagnosed when the combination
of hyperglycemia (high blood sugars), ketones on urinalysis and
acidosis are demonstrated.
Alcoholic ketoacidosis(AKA)
Although the general physiological factors and mechanisms
leading to AKA are understood, the precise factors have not
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been fully defined. The following are the 3 main predisposing
events:
Delay and decrease in insulin secretion and excess glucagon
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Alcohol dehydrogenase metabolizes alcohol to acetaldehyde
in the cytoplasm of hepatocyte mitochondria.
Acetaldehyde is metabolized further to acetic acid by
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Alcoholic ketoacidosis(AKA)
The decreased ratio of NAD+ to NADH has the following
implications:
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Impaired conversion of lactate to pyruvate with an increase in
serum lactic acid levels
Impaired gluconeogenesis because pyruvate is not available as
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ketoacids.
Moreover, volume depletion increases the concentration of
counter-regulatory hormones, further stimulating lipolysis and
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drinking binge suddenly decreases energy intake because of
abdominal pain, nausea, or vomiting.
In addition, AKA is often precipitated by another medical
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high rate of fatty acid oxidation. The pathway of ketogenesis
involves synthesis and breakdown of 3-hydroxy-3-
methylglutaryl-CoA (HMG-CoA) by two key enzymes, HMG-